Despite large immunization programs, pathogen infections continue to cause significant human illness and death worldwide. The primary goal of emerging vaccine design is to establish long-lived depots of safe pieces (antigens) of deadly pathogens that will stimulate protective immune responses. However, the ability of long- lived depots of non-replicating pieces of pathogens to stimulate protective immune responses has been hampered by limitations of existing experimental models. Our studies have used infection of mice with influenza virus to demonstrate the unique ability of this experimental model to naturally form long-lived antigen depots capable of recruiting large numbers of new CD4 T cells into the anti-viral immune response as the new CD4 T cells are exported to the periphery from the thymus after clearance of live virus. Importantly, the latecomer CD4 T cells generated to these residual antigen depots constitute upwards of half of the total immune CD4 T cell population following experimental influenza infection. Thus, the unique aspects of our experimental influenza virus infection model provides a powerful tool for probing the potential for natural depots of residual antigen to enhance the production of immune CD4 T cell populations capable of helping protect against virus infections. These proposed studies have been crafted to determine if residual antigen depots serve to generate immune CD4 T cell populations that are flexible enough to provide a diverse range of protective functions against challenge virus infections. The results of these studies will provide critical information for the rational design of safe protein subunit vaccines designed to target non-replicating pathogen antigens to beneficial antigen depots for inducing protective anti-viral immunity against a wide range of virus strains. Additionally, our preliminary studies have demonstrated that significantly larger numbers of new CD4 T cells emerging from the thymus are capable of being recruited into the protective immune response by residual antigen depots. Thus, emerging therapies aimed at increasing thymus output of new CD4 T cells, particularly in the elderly and immune compromised patients, have the potential to enhance immunity to infections and vaccinations that result in beneficial residual antigen depots. Public Health Relevance: Despite current immunization programs, viral infections continue to cause significant human illness and death worldwide. To augment conventional immunizations we need new vaccines that will target the conductors of the immune system - CD4 T cells. The studies proposed here will help us understand how to target effective CD4 T cell immunity, protect against a broad variety of pathogens, and lay the foundation for research and development of new vaccine strategies to combat deadly infections.